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Summary infectious diseases and oncology
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Summary of 23 pages for the course Infectious disease and oncology at RuG (Complete summary)
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SUMMARY infectious disease and oncologyLearning outcomes:
1. Distinguish the pathogenesis of different bacterial, viral and fungal infections
2. Discuss the pharmacology (working mechanism, important clinical applications, side effects
and pharmacokinetic aspects) of classes of drugs used to treat infectious diseases and tumors
3. Choose a course of treatment for common infectious disease and cancers by weighing the
advantages and disadvantages of chemotherapeutics in light of pathogensis and patient
history
4. Discuss the problem of drug resistance with respect to the treatment of infectious diseases
and explain the preventive policies in place in hospital and pharmacies
5. Describe examples of immunopharmacolgical therapies to treat autoimmune diseases and
cancer, based on the disussed studie cases.
Lecture 1 infectious diseases and oncology introduction
Important to memorize:
- Bactericidic/bacteriostatic (=eliminate by immune mechanism)
- Unique pathway cell wall synthesis inhibition, folic acid synthesis inhibition, ergosterol
synthesis inhibition, binding to membrane ergosterol, HIV protease inhibition and
neuraminidase inhibition.
- Similar: dihydrofolate reductase inhibition, topoisomerase inhibition, protein synthesis
inhibition and DNA/RNA polymerase.
- Same pathway: dihydrofolate reductase inhibition, anti-metabolite nucleotides and DNA
polymerase inhibition.
- Principles of antimicrobial therapy (targeted, empiric, prophylactic, effectiveness (time
(T>MIC) and concentration dependent (Cmax/MIC) and both (AUC/MIC), post-antibiotic
effect= T*C, combination of drugs (reasons))
- PAE drugs: aminoglycosides, tetracyclines, carbapenems, quinolones and rifampicin.
Mechanism: slow recovery, binding site or new enzymes.
- IV-> critical patient bacterial meningitis or endocarditis
- TDM
- Most antimicrobial agents are well distributed to most body tissues and fluids, except
cerebrospinal fluid!
- Bayesian simulation: application of population PK model in combination with individual
patient data (Cplasma) dose adjustment. Know advantages.
- Bacteriostatic agents can antagonize the action of bactericidal cell wall active agents!- >
general rule not combine cid and static !!
- Tolerance development, antibiotic resistance+ mechanism (enzyme production (B-lactam),
change target binding spot, decreased accumulation, correction of damage, decrease
apoptosis)
- ESKAPE (enterococcus faecium, staphylococcus aureus, klebsiella pneumoniae,
Acinetobacter baumanni, pseudomonas aeruginosa, enterobacter species.
- Superbugs: MRSA (methicillin resistant staphylococcus aureus),ESBL (extended spectrum
B-lactamase), MDRAB (iraqibacter), VRE (vancomycin resistant enterococcus), CRE
(carbapenem resitent entereobacteria) and CRAB (carbapenem resistant acinetobacter)
- Zosurabalpin: defeated high drug resistant strains of carbapenem-resistant Acinetobacter
baumannii (CRAB) blocking transport of bacterial lipopolysaccharide from the inner
membrane to its destination on the outer membrane.
- Gram-negative (not stained (red pale), LPS, treatment is harder, inner and outer
membrane) and gram-positive membrane (stained, more peptidoglycan, only innerlayer)
both (cocci, antibacterial resistance via plasmids)
- Gram positive cocci: staphyloccus aureus (skin, wound, osteomyelitis, endocarditis),
streptococcus pyogens (wound, skin), streptococcus pneumonia (respiratory),
streptococcus viridans (dental, endocarditis) and enterococcus (urinary and endocarditis)
- Gram positive bacillus: corynebacterium diphtheriae (diphtheria), bacillus anthracis
- Gram positive bacillus anaerobe: clostridium spp. (pseudomembranous colitis)
, - Gram negative cocci: Neisseria meningitidis (meningitis), Neisseria gonorrhoeae,
moreaxella catarrhalis (respiratory)
- Gram negative: haemophius influenza, helicobacter pylori (ulcers), coliform bacteria (e.coli,
klebsiella spp. Proteus spp. Slamonella (diarrhea), shigella ssp (diarrheoa).),
pseudomonas aeruginosa (urinary, respiratory and wound infections).
- Gram negative bacillus anaerobe: bacteroides fragilis,(GI, dental and gynecological)
propionibacter acnes
- Spirochetes: terponema pallidum (syphilis), borellia burgdorferi (lyme)
- Intracellular pathogen: legionella pneumonphilia (legionnaires), mycoplasma
pneumoniae, chlamydia ssp (respiratory and urthritis). and rickettsiae (typhus, Q fever).
- Mycobacteria: waxy lipid rich outer layer, acid-fast staining 9, TBC, leprosy.
- Opportunistic infection: an infection with MO that doesn’t normally bother a person, but
which can infect if the patient has low resistance or local damage.
Lecture 2 cell wall and membrane as target
Important to memorize:
- Structure penicillin (3C,thalizodie ring, B-lactam ring, COOH, amide, cis stereo), enzyme
penicillin G acylase (PGA)
- Gram negative (D-glutaminezuur and meso-diaminopimeline zuur)/gram positive bacteria
(L-lysine and D-glutamine)
- Crosslinks are made by transpeptidase (PBP), B-lactam antibiotics inhibit PBP!
- Slide 27 overview drugs
- 3 reasons for low acid stability: B-lactame ring sensitive for nucleophilic attack, resonance
of amide not possible and influence of acyl side chain (neighbouring effect)
- How to reduce acid sensitivity electron withdrawing group
- More polar R->poor adsorption (better activity against gram negative bacteria)
- Mechanism of action B-lactamase (ring opening), design lactamase resistant penicillin!
- B-lactamase: based on structure and chemical similarities to D alanyl and alanine fairly put
crosslinking peptidoglycan network.
- How to influence the B-lactamase sensitivity: steric hindrance+ lactamase inhibitor (inhibit
mainly penicillinases A, no bacterial function on its own)
- Reducing B-lactamase sensitivity: pro big at same time electron withdrawing, contra: PK
negatively influenced.
- First generation penicillin poor activity against gram negative bacteria since
coating(hydrophobic) of cell membrane and negatively charge of cell membrane. How to
broad spectrum: add more hydrophobic groups: better against gram+, more hydrophilic
groups no effect Gram+ and enhance effect Gram-
- Penicillin G: good distribution, active against Gram+
and Gram-, fast excretion via kidney, nontoxic,
unstable at acidic conditions, sensitive to all known
B-lactamases, less active against gram- bacilli and
frequently allergic reactions.
- Lactamase inhibitors (suicide
inhibitors,irreversible): clavulanic acid,
sulbactam, tazobactam.
- Clavulanic acid often combined by
amoxicilline to overcome resistance
against klebsiella, haemophilus influenza
and bacteroides fragilis and more.
Clavulanic acid is a suicide inhibitor,
, irreversible. B-lactam ring is opened by serine residue, this will react further with a
nucleophile on the enzyme leading to a frozen structure.
- Sulbactam: added to ampicillin
- Sultamicilline: oral, ester of ampicillin and sulbactam
- Which antibiotic? Spectrum, absorption, SE, stability, patient
- Resistance occurs via: B-lactamase, modification PBP, shielding PBD by mutation in cell
membrane or wall and enhanced efflux of antibiotics via exporter.
- Structure cephalosporins: (4C=dihydrothiazide, B-lactam ring, COOH, bicyclic system and
stereochemistry of side chains and rings) (less tension, more stable)
- Positions where changes in the molecule can occur slide 71
- Cephalosprin C: inhibition of the cell wall transpeptidase enzyme: less reactive B-lactam
ring and good leaving group.
- Cephalosporins: all not metabolized by the body! Allergy and over-sensitivity are less a
problem as compared to penicillin.
- Cephalexin: very popular cephalorporin, first generation. Indications: airway infections, skin
infections, bladder infections.
- Second generation cephalosporins: more bulky more resistance against B-lactam (first
and second generation poor penetration CNS).
- Third (OK penetration CNS)and fourth generation
(both poorly absorbed): cephalosporins:
iminomethoxygroup on a-position: improved stability
towards B-lactamse. Aminothiazolring: enhanced
penetration through the outer membrane. Enhanced
affinity for PBP and cefepime(4e) is a zwitterion->
improved passage through the outer membrane of
gram- bacteria.
- Ceftobriprole: fifth generation cephalosporin (backup), anti-MRSA cefalosporin (resistant
against staphyloccous B-lactamse and inhibits staphylococcus PBP2a. indication: skin, soft
tissue infections.
1e and 2e generation-> poor
penetration CNS
3e generation OK in CNS
2e and 3e generation poor
absorbed. Not metabolized
body!!! Better B-lactamse
resistant
- First generation: bladder and airway infections
- Second generation: very B-lactamase resistance.
- Third generation: osteomyelitis, meningitis, urinary tract infection
- Fourth generation: back-up antibiotics.
- General side effects cephorins: SE: bleedings, kidney damage and GI problems (less than
penicillin) less allergy and oversensitivity compared to penicillin.
- Carbapenems (meropenem, ertapenem and
imipenem): administration only IV, indication: only if all
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